Abstract

Doxorubicin (dox) is a widely used oncology agent known to induce dose-limiting cardiomyopathy, driven partially by the excess production of reactive oxygen species (ROS) in mitochondria. Cardiomyocytes are particularly sensitive to ROS due to higher densities of mitochondria and lower concentrations of antioxidants. The incidence of dox induced cardiomyopathy is lower in reproductively mature women compared to age matched men, while pre-pubescent and post-menopausal females are more sensitive. Previous studies have associated reproductive hormone levels with differences in cardiosensitivity based on gender and age. This is the second part of a two part study investigating the role that reproductive hormones play in dox induced cardiotoxicity in female, tumor-bearing spontaneously hypertensive rats (SHRs). In the current study, we investigated the impact of natural hormone cycling on dox induced cardiomyopathy. Before beginning the experiment, regular hormone cycling was established by monitoring daily changes in the estrous cycle by way of vaginal cytology. The animals were organized by phase (proestrus, estrus, metestrus, or diestrus) and implanted with SST-2 cells, a syngeneic breast cancer cell line derived from a SHR. Tumor-bearing animals were administered a single dose of saline, dox, the cardioprotectant dexrazoxane, or a combination thereof and monitored for 14 days. Daily vaginal cytologies were obtained throughout the experiment to monitor estrous cycling as a means of tracking hormone fluctuations. Serum was collected at various time points to correlate estrous cycling with circulating hormone levels (E2 and P4) and measure the cardiac health indicator cardiac troponin I (cTnI). In all hormone groups, dox treatment resulted in a net loss in bodyweight and significant anti-tumor activity, as measured by tumor volume, compared to respective saline controls. Interestingly, animals treated with saline in metestrus displayed increased tumor volumes compared to animals in different estrous phases. We are currently evaluating cardiac status by echocardiogram, histopathology, and cTnI. We are also measuring serum E2 and P4 hormone levels in an effort to understand the relationship between cardiomyopathy and circulating hormones.